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Implementing a National Cancer Clinical Trials System for the 21st Century
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From page 1...
... John Mendelsohn, chair of the IOM National Cancer Policy Forum (NCPF) and director of the Khalifa Institute for Personalized Cancer Therapy at the University of Texas MD Anderson Cancer Center, opened the workshop with a brief overview of the 2010 IOM consensus report titled A National Cancer Clinical Trials System for the 21st Century: Reinvigorating 1
From page 2...
... . Recognizing the recent transformative advances in cancer research that necessitate modernization in how cancer clinical trials are run, as well as inefficiencies and other challenges impeding the national cancer clinical trials program, the NCI asked the IOM to develop a set of recommendations (summarized in Appendix B)
From page 3...
... IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 3 BOX 1 Overview of Key Achievements Since 2010 •  onsolidated and integrated cooperative groups and C operations • Substantially reduced median time to trial activation • Improved information technology systems •  mproved intellectual property terms for collaborative I research • mproved processes and timelines for the two NCI central I institutional review boards • ncreased reimbursement to sites for large phase II studies I and additional funding for select phase III trials based on complexity • New guidance from the FDA on data collection •  ew initiatives and resources to support the development of N precision medicine BOX 2 Overview of Suggestions Made by Individual Participants •  nhance and expand collaborations among stakeholders E (e.g., the NCTN, the pharmaceutical and diagnostics indus tries, federal agencies, and patients) • Expand use of innovative trial designs • Develop and validate technologies for precision medicine • Define criteria for use of genomic and other biomarker tests •  dequately cover the costs of tumor profiling and rebiopsy A if necessary •  reate a centralized clearinghouse for annotated genetic C profiles of patients' tumors •  nsure that endpoint measurement is free of bias in trials E assessing tumor response or progression •  ssess quality-of-life issues in cancer clinical trials A •  ngage patients in trial design to enhance participation E •  onduct a pilot study to assess whether reimbursing oncol C ogists for the time it takes to inform patients about clinical trials increases patient accrual
From page 4...
... should lead treatment trials at concept stage a transagency effort to streamline and • Developed coordinated processes for development/review of trials under the FDA Special Protocol harmonize government oversight and Assessment (SPA) regulation of cancer clinical trials • Developed adult and pediatric NCI central IRBs, with major improvement in review timelines and accreditation by the Association for the Accreditation of Human Research Protection Programs • Working with FDA to coordinate early review of investigational devices (biomarker tests)
From page 5...
... in the Cancer Therapy Evaluation Program relating to drug development; for Biomarkers/Tissues -- no blocking IP; royalty-free nonexclusive licenses • 6-month absolute deadline for CRADA negotiations with pharmaceutical companies 5: NCI should mandate submission • Revising the Request for Applications for U24 grants (cooperative agreements) for National of annotated biospecimens to Specimen Banks for NCTN Groups to include common operating procedures for samples collected high-quality, standardized central from patients in NCTN and other NCI-supported trials biorepositories when samples are • Developing a common process and procedures for requesting biospecimens banked from NCI collected from patients in the course clinical trials of Group trials and should implement • Developing a shared IT infrastructure to enhance specimen inventories new funding mechanisms and policies to support the management and use of those resources for retrospective correlative science 5 continued
From page 6...
... investigations associated with NCTN trials development of national unified • Working with the National Library of Medicine and the Association of American Cancer Institutes standards to develop the Cancer Trials Reporting Program (CTRP) database to provide accrual information related to all NCI-supported clinical trials with full accrual reporting to begin in 2013 8: NCI should reevaluate its role in the • CTAC Strategic Planning Working Group was established to evaluate the overall effectiveness of clinical trials system studies conducted by NCTN • Revamped prioritization process for phase 3 and large phase 2 treatment and control trials through disease and modality-specific Steering Committees to ensure most important trials are given highest priority • NCI represents Institute priorities for the public program on the Steering Committees and facilitates implementation of prioritized clinical trials
From page 7...
... Goal 3: Improve prioritization, selection, support, and completion of cancer clinical trials Recommendation NCI Response as of February 2013 9: NCI, Cooperative Groups, and • Modernizing the clinical trials IT infrastructure by implementing a common clinical data physicians should take steps to increase management system to be used across the NCI-supported clinical trials system the speed, volume, and diversity • Enhancing trial participant diversity through support for Minority-based Community Clinical of patient accrual and to ensure Oncology Programs, Patient Navigator Research Program, and other NCI programs high-quality performance at all sites • Working with patient advocates in concept development and accrual planning, along with Groups, participating in Group trials Disease Steering Committees, and Patient Advocate Steering Committee 10: NCI should allocate a larger • Developed targeted initiatives that have increased reimbursement to sites for patients on large portion of its research portfolio to phase II studies and additional funding provided for select phase III trials based on complexity as the Clinical Trials Cooperative Group well as the funding for critical biomarker, imaging, and QOL studies Program to ensure that the Program • Changes in the funding model for the new Funding Opportunity Announcement: has sufficient resources to achieve its o Increased reimbursement for high-performing sites (aimed at 40% accrual) unique mission o Need for additional infrastructure support with proposed budget increased to support better reimbursement but lower total level of accrual o Increase in core resources for genomic correlative studies 7 continued
From page 8...
... 8 TABLE 1 Continued Goal 4: Incentivize the participation of patients and physicians in clinical trials Recommendation NCI Response as of February 2013 11: All stakeholders should work to • Created the Clinical Investigator Team Leadership Award to promote collaborative science and ensure that clinical investigators have recognize outstanding clinical investigators; annual awards made since 2009 adequate training and mentoring, paid protected research time, necessary resources, and recognition 12: Health care payment policies • Working with the NIH as well as across HHS agencies and with other federal agencies to help define should value the care provided to and shape national policy on clinical trials and reimbursement as well as to educate patients and patients in clinical trials and adequately payers regarding the benefit of clinical trials compensate that care • Working with FDA to facilitate incorporation of genomic tests into definitive clinical trials and the development of companion diagnostics SOURCE: Doroshow presentation (February 12, 2013)
From page 9...
... BOX 3 Reconfigured Groups of the NCTN •  lliance for Clinical Trials in Oncology (consolidation of A Cancer and Leukemia Group B, the North Central Cancer Treatment Group, and the American College of Surgeons Oncology Group) •  hildren's Oncology Group C •  COG-ACRIN Cancer Research Group (consolidation of E the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network)
From page 10...
... These centers will offer a platform for sustained, cutting-edge scientific effort and enhance interactions across groups and with cancer centers, he stressed. The NCI has also expanded its Cancer Trials Support Unit to enable centralized administrative and regulatory functions for clinical trials.
From page 11...
... It will also facilitate more clinical trials of rare cancers by enabling rapid approval of a trial as patients with these rare diseases are encountered in the clinic, he added. "Now that we're going to have these small and molecularly defined populations, it's rather critical that institutions have the ability to open trials when they find the right patients, because we probably will have many more trials with such small populations," said Jeffrey Abrams, associate director of CTEP in the Division of Cancer Treatment and Diagnosis at the NCI.
From page 12...
... . SOURCES: Doroshow with type and lines 11, presentation (February blocked over Reprinted with permission from the raster image Journal of the National Cancer Institute.
From page 13...
... The NCTN groups and pharmaceutical industry organizations have complementary skills that can be leveraged to deliver innovative trials, he said, and the extensive network of academic and community practices within the NCTN makes it easier to conduct clinical trials on rare diseases. "Cooperative groups can reach out to patients quickly," Capdeville noted.
From page 14...
... or processes that support: • Data collection: remote data capture • Data coding: standard libraries -- common toxicity criteria •  ata management: discrepancy, delinquency, communica D tion, correction, and preparation of data for analysis Core benefits of CDMS on NCI-supported multicenter trials: • Reduces training costs and overall cost of data management • Reduces risk of data delinquency and/or discrepancy • Reduces time/effort to correct/complete data •  educes delays in obtaining science and safety results and R improves trial management and decision making Other benefits of CDMS on NCI-supported multicenter trials: •  upports/complements transformation of groups into a new S "network" program •  eets FDA and other federal requirements for e-data cap M ture, security, and transfer • Promotes data sharing •  ets the stage for further infrastructure improvements, such S as integration with expedited serious adverse event report ing, remote auditing, and electronic filing for FDA reports SOURCE: Doroshow presentation (February 11, 2013)
From page 15...
... Doroshow pointed out that the NCI has harmonized all its guidelines for programs engaged in the conduct of clinical trials, so that the appropriate incentives are in place for collaboration among investigators in different programs. In addition, the NCI, in collaboration with the CEO Roundtable on Cancer, developed START clauses for company and academic collaborations to speed clinical trial negotiations (NCI and CEO Roundtable on Cancer, 2008)
From page 16...
... New aggressive timelines for getting clinical trials under way are also encouraging more industry partners to participate, Abrams pointed out. "Our industry colleagues have told us that ‘time is money.' We can't sit around waiting a very long time for NCI studies to get up and running." Genentech has had several productive clinical trial collaborations with NCTN, Horning noted, and she offered several lessons learned from those collaborations.
From page 17...
... There also should be prospective agreement between a clinical trials group and an industry sponsor of a registration trial regarding data collection and curation; safety reporting and access to records; and communications, publications, and presentations; all of which should ensure that data are of high quality, reported in a timely fashion, "fit for purpose," and compliant with regulatory requirements, Horning said. (A more extensive discussion of this trial design issue is described below in the "Regulatory Issues" section.)
From page 18...
... She also appreciated the NCI's revised IP stipulations in the CRADAs, which recognize the value to industry of annotated specimens and what they can reveal in the current era, in which predictive diagnostics have become more essential to drug development and therapeutic approval. In addition, Horning applauded the shortened timeline the NCTN has recently instituted between concept submission and trial activation.
From page 19...
... Capdeville described the RATIFY2 trial, an innovative, global phase III trial that Novartis is conducting in collaboration with CALGB (Cancer and Leukemia Group B; now part of the Alliance for Clinical Trials in Oncology)
From page 20...
... This required patients to consent to their samples being used not only for the phase III clinical trial, but also for the later bridging study, as well as central storage of all tumor samples. The study is ongoing, but Capdeville listed several lessons that have already been learned from the collaboration: • Keep the data flow as simple as possible.
From page 21...
... These centers were the sites of Dana-Farber's clinical trial activity, except for phase I studies, which stemmed from the institute's Early Drug Development Center. Although the centers were multidisciplinary, including surgery, radiation, oncology, nursing, pharmacology, and medical oncology, "they were becoming somewhat siloed around their particular cancers that they were interested in," said Benz.
From page 22...
... They are also well versed in biomarkers and clinical biomarker assays and have access to clinical specimens through academic collaborations with a broad network of investigators. The Belfer Institute has been partnering with large pharmaceutical firms such as Merck and Sanofi to identify and validate new drug targets and delineate a clinical path for drugs in clinical trials.
From page 23...
... Anderson stressed that one should consider not only financial capital but also human capital when evaluating whether collaborations furthered by venture medical philanthropy will be productive and valuable. If patients trust advocacy organizations and foundations, they will be more willing to participate in the research they sponsor; these organizations "are really changing the game of clinical trial recruitment," Anderson said.
From page 24...
... Most TIMI trials are sponsored by industry and enroll between 15,000 and 25,000 patients per trial. Sabatine explained how the TIMI Study Group operates and how it collaborates with industry in conducting clinical trials.
From page 25...
... TIMI physicians include • clinicians on the staff at Brigham and Women's Hospital; • global principal investigators for trials who come from the faculty at Harvard Medical School and dedicate between 75 and 80 per cent of their time to research; and • clinical trialists (TIMI investigators) , who are highly experienced in the design of clinical trials and work daily with the senior project director on trial implementation.
From page 26...
... "We have very frank conversations at the beginning of any potential marriage with our sponsors that set the boundaries and reinforce respect for and trust in the Independent TIMI SPONSOR Biostatistics CEC IDMC JOINT MANAGEMENT TEAM Safety Desk Biweekly Mtgs TIMI Study Chair, PI, Co-PI's, Dir Ops, Sr PD Biomarker and EXEC CMTE Sponsor Med & Ops Leads Genetic Cores 5-7 members; meet 6x/yr Study Chairman, PI, Other MDs, Sponsor Statistics JOINT WORKING GROUP Weekly Mtgs Study Drug STEERING CMTE Operational & Med Personnel ~40 members; meet 3x/yr EC + NLIs IXRS CLINICAL SITES Monitoring Core Safety Labs Database FIGURE 2  TIMI trial organization. NOTE: CEC = Clinical Events Committee; Dir Ops = Director of Operations; EC = executive committee; EXEC CMTE = executive committee; IDMC = Independent Data Monitoring Committee; IXRS = interactive voice recognition/website system; MDs = medical doctors; Med = medical; Mtgs = meetings; NLI = national lead investigator; Ops = operations; PI = principal investigator; Sr PD = senior project director; R02456 STEERING CMTE = steering committee; TIMI = Thrombolysis In Myocardial Infarction; x/yr = times per year.
From page 27...
... The Timeline for Cancer Drug Development To provide a perspective on the challenges involved in conducting efficient cancer clinical trials, Joseph DiMasi, director of economic analysis at the Center for the Study of Drug Development at Tufts University, presented data on clinical development and approval times for cancer drugs. He showed that antineoplastic drugs have long development timelines compared with most other therapeutic classes, and that development times are
From page 28...
... More detailed analysis fully editable vectors revealed that drugs for bloodsome typenearly four times more likely to be cancers are is outlined approved than those for solid tumors, and that the risk of drug development failure varies significantly by cancer type, but not by molecule size. DiMasi also showed that despite long development times, the number of anticancer drugs approved in 2012 was more than twice the average annual rate for the previous decade.
From page 29...
... FOSTERING INNOVATION As a preface to discussing the IOM recommendation to incorporate innovative science and trial design in cancer clinical trials, one session of the workshop was devoted to exploring the latest advances in "precision" medicine (also referred to as "personalized" medicine) and the challenges in implementing these new technologies in clinical care.
From page 30...
... These challenges include acquiring tumor samples, the genetic heterogeneity of those samples, developing innovative clinical trial strategies that can apply the genetic findings, and addressing issues related to quality control and reimbursement for biopsies and tests. Collecting Biospecimens Among the logistical challenges is the need to obtain consent from patients to submit to biopsies and extensive genetic testing of their tumors and to appropriately counsel them about what the results mean.
From page 31...
... Others may not have enough tissue for the multitude of tests that may need to be done by multiple labs, added Vincent Miller, senior vice president of clinical development at Foundation Medicine, Inc. Researchers continue to identify relevant new genetic alterations, and the tests for those changes continue to be developed.
From page 32...
... Miller added, "We need to develop common criteria for the testing we accept for our clinical trials." Lisa McShane, mathematical statistician at the Biometric Research Branch in the Division of Cancer Treatment and Diagnosis at the NCI, noted that often there is variability in results from laboratories doing the same test, which could be an argument for central testing, although this could raise logistical problems. She pointed out that more than a dozen years after the first test for HER2 (human epidermal growth factor receptor 2)
From page 33...
... "It was not so surprising that these patients responded -- the surprise was that they had this mutation we didn't know about before," Solit said. Given the value of such discoveries, several speakers suggested that there is a need to develop and validate profiling technologies so that all cancer patients can have their tumors genetically profiled and receive cancer treatments matched to their profile.
From page 34...
... "Our approach has been to link genome technology, clinical oncology, cancer biology, and information science to make this test applicable to routine clinical practice," Miller said. Sometimes Foundation Medicine's assay reveals aberrations that could potentially be targeted by drugs that are in clinical trials, but the trials may not be available locally, and patients are not always entered into trials, Miller noted.
From page 35...
... Foundation Medicine also works with pharmaceutical firms to conduct prospective studies in which individuals are assigned to a line of therapy based on the presence or absence of one or more alterations in a gene or a series of genes, Miller said. Innovative Trial Designs Solit's findings from exceptional responders in clinical trials also suggest the need for an innovative clinical trial design that tests the same agent on people with a wide range of cancer types, he stressed.
From page 36...
... The screening protocol should be separated from the treatment protocol. Otherwise, we're not going to be able to find enough patients for the clinical trials we want to do." For patients whose tumors have multiple drivers, it will be difficult to decide how to fit them into basket studies that offer a treatment targeting only one of the drivers.
From page 37...
... For example, patients could be randomized to receive standard therapy with or without the new targeted agent. McShane stressed that "innovation is great, but we have to make sure the innovative methods still answer the questions that need to be answered." She gave examples of other innovative biomarker-based clinical trial designs (Freidlin et al., 2010)
From page 38...
... But he did have an atypical KRAS7 mutation, so the patient was enrolled in a clinical trial of an agent that targets the KRAS signaling pathway. Abrams also described two innovative trials currently in the planning stage at the NCI's Cancer Therapy Evaluation Program.
From page 39...
... "Genomic profiling is becoming more readily available, but a bigger obstacle to delivering optimal care to patients is actually getting the right drug," said Richard Schilsky, chief medical officer at ASCO. "Doctors are scurrying around trying to find drugs that are suggested by these tests, whether it's for purposes of a clinical trial or for off-label use." Roy Herbst, professor of medicine and pharmacology and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, added that in the ALChEMIST trial, only about 15 percent of patients who have their tumors screened will be eligible for treatment in the trial.
From page 40...
... to include common operating procedures for samples collected from the NCTN and other NCI-supported trials. In addition, the NCI initiated its Biomarker, Imaging, and Quality of Life Studies Program to ensure that critical correlative studies could be incorporated in a timely manner into phase III and large, multi-institutional phase II trials during the process of concept development.
From page 41...
... Patricia Ganz, distinguished university professor at the University of California, Los Angeles, Schools of Medicine and Public Health and director of cancer prevention and control research at the Jonsson Comprehensive Cancer Center, added a plea that any such clearinghouse fully annotate specimens and include information such as concomitant medications, health behaviors, environmental exposures, and other relevant host factors that might influence the outcome for cancer patients. IMPROVING PRIORITIZATION, SELECTION, SUPPORT, AND COMPLETION OF TRIALS The IOM consensus report emphasized the need for sufficient funding and resources to support an effective and efficient national clinical trials system, as well as the need to prioritize trial concepts.
From page 42...
... Another task of the working group is to provide strategic advice to enhance NCTN clinical trial operations, such as collaboration and timeliness. Twenty-eight extramural members from key stakeholder groups comprise the NCTN Working Group, including NCTN group chairs and statisticians, Community Clinical Oncology Program (CCOP)
From page 43...
... For the clinical importance criterion, the working group came up with the concept of life-years saved to discern benefit to the patient or the population. BOX 5 Criteria for Evaluating NCTN Trials •  easibility (accrual difficulty, time and cost to implement at F sites)
From page 44...
... But the working group thought there was still room for improvement and recommended smaller, innovative, and more nimble randomized phase II trials, such as molecularly driven trials, trials that discover or validate biomarkers, trials aimed at limiting toxicity and improving quality of life, and survivorship studies. The working group concluded that the breast cancer SSC could provide more strategic guidance for concept selection and for developing standards to improve trial design, perhaps by tapping into the resources of other groups, such as task forces, working groups, or clinical trial planning meetings.
From page 45...
... Quantity is less important than quality and, less obviously, it's drowning out the useful information by creating too much noise." Lessons from the National Clinical Trials System in the United Kingdom Richard Kaplan, associate director of the UK National Cancer Research Network (NCRN) and UK Clinical Research Network and senior scientist at the Medical Research Council Clinical Trials Unit, described how the UK NCRN operates and how it differs from the U.S.
From page 46...
... NCTN. In the United Kingdom, virtually all of the clinical costs for patients in cancer clinical trials are covered by the NHS.
From page 47...
... "League tables" that compare performance are compiled and made public. In 2001, when the UK clinical trials system was restructured and the NCRN was established, a major goal was to increase patient accrual to cancer clinical trials.
From page 48...
... In response to a question from Pazdur about the type of cancer trials conducted in the United Kingdom, Kaplan noted that "much of the thrust of the CSG has been new drug development, with more than half of the trials being phase III trials," although he added that the number of phase II trials is increasing. Herbst asked how biomarker tests for patient stratification are paid for in UK cancer trials.
From page 49...
... Doroshow noted that industry is not likely to do trials of agents for more than one histological type of cancer, so these types of trials are more appropriate for the NCTN. "So many of the advances in cancer medicine and clinical trials research have been multidisciplinary in nature and it's not in industry's business model to do those kinds of studies," he said.
From page 50...
... Now, more than 90 percent of pediatric cancer patients in the United States receive treatment at COG sites and more than half are enrolled in COG trials. Still, cancer remains a leading cause of death in children, "so the work is just really beginning," Adamson said.
From page 51...
... Boosting Patient Accruals Abrams said that the number of cancer patients enrolled in NCTN trials has declined in recent years, to about 20,000 per year. Abrams reiterated that over the past 10 years, the United Kingdom was able to substantially boost the rate of patient participation in clinical trials through financial reimbursements.
From page 52...
... That patient community doesn't exist if we only look to the large cancer centers. We have to be able to reach out to every hospital and other settings where patients live and convince them they need to participate in clinical trials if we are to achieve [real progress]
From page 53...
... Gavin responded that patient advocates advise patients to talk to their oncologists about options for a clinical trial as a possible treatment option and encourage them to "do their homework" beforehand by exploring websites that list information about trials. Increasing Physician Participation Participants at the workshop also voiced concerns about a decline in the number of physicians willing to engage in clinical trials.
From page 54...
... Consequently, investigators are "having to negotiate and see affirmation of the role of clinical trials within those systems," she said. Stephen Grubbs, principal investigator of the Delaware Community Clinical Oncology Program and managing partner at Medical Oncology Hematology Consultants, PA, said these mergers are a major problem in the current era of tight budgets because hospital administrators often are not willing to devote resources to cancer research.
From page 55...
... But Benz pointed out that reimbursement is lacking for tasks related to acquiring and testing specimens for patients in clinical trials, which go beyond routine clinical management. "Something needs to be built into the reimbursement system because the mechanisms for funding that in a community setting are almost non-existent unless they have some formal collaborative relationship with a big cancer center, which immediately shrinks down the number," he said.
From page 56...
... Eligibility for NCORP community sites is based on the capacity to participate in cancer research, including • clinical research experience (clinical trial accrual) ; • cancer care delivery research infrastructure; • available study populations; and • senior leadership/organizational support.
From page 57...
... NCORP has also been promoting the participation of underserved populations and incorporating disparities research questions into clinical trials and cancer care delivery research. Grubbs noted the diversity of different underserved communities, from rural populations and Native Americans to African Americans and Hispanics.
From page 58...
... REGULATORY ISSUES Under the broad goal of improving the speed and efficiency of clinical trials, the IOM consensus report included a recommendation for a transagency effort to streamline and harmonize government oversight and regulation of cancer clinical trials (IOM, 2010b)
From page 59...
... Jessup added that in late 2010, the FDA Office of In Vitro Devices began to enforce its oversight authority for the safety of diagnostics used for medical decision making in clinical trials. Biomarker tests used for medical decision making, even within a clinical trial, are required by law to be performed in a CLIA-certified laboratory.
From page 60...
... . Solit stressed that biomarker validity is more important for late-stage clinical trials.
From page 61...
... So, your philosophy hasn't hit the practice of medicine yet, unfortunately," he said. Regulatory Oversight for Trials of Small Subsets of Cancer Patients Participants discussed the appropriate regulatory oversight for trials of small subsets of cancer patients.
From page 62...
... The ASCO study reanalyzed multiple clinical trial toxicity databases and examined various sampling methods to determine if a more streamlined and "optimized" approach to data collection would provide sufficient safety data to support supplemental applications. This study found that capturing excess Grade 1 or 2 adverse events did not appear to add to the known safety profile, and that the probability of missing a previously unrecognized, clinically significant Grade 3 or 4 adverse event was low when the optimized data collection approach was used.
From page 63...
... Sherman, of the FDA, pointed out during her presentation that the purpose of the draft FDA guidance is to help clinical trial sponsors determine the amount and types of safety data that should be collected during late-stage premarket and post-approval clinical investigations. She said this draft guidance makes clear that sponsors can use a variety of approaches to fulfill their monitoring responsibilities, and that sponsors may request different reporting formats or frequencies for adverse event reporting either by describing the method in the protocol or by requesting a waiver.
From page 64...
... . Two more recent reviews of cancer clinical trials found more than 90 percent correlation in the hazard ratios between blinded independent central reviews and local assessments of progression of solid tumors (Amit et al., 2011; Zhang et al., 2013)
From page 65...
... He noted that in one ECOG clinical trial, two radiologists reading the images disagreed almost half the time. "Does anyone seriously believe adding a third radiologist's readings will be of statistical benefit?
From page 66...
... The risk of bias comes from how the oncologist interprets that information that comes from those radiology reads." But he added that in large clinical trials, the bias contribution of a single oncologist would be minor and wouldn't be likely to influence the outcomes. "If all the participating physicians in the trial have a systematic bias, then that trial was doomed from the start.
From page 67...
... recently reviewed and revised its clinical trials legislation to take a more risk-based approach, and the EMA is trying to foster earlier and more continuous communications between regulators and sponsors. But he added that although the EMA will give advice to sponsors about trial design and conduct, that advice is optional and not binding; individual countries have not given the agency authority over design, approval, and conduct of clinical trials.
From page 68...
... For example, the FDA revoked approval of bevacizumab for breast cancer treatment because new studies did not show improvement in overall survival, but the EMA found that the benefits of bevacizumab in combination with paclitaxel outweighed its risks and approved the combination (Burstein, 2011; EMA, 2010)
From page 69...
... According to Pignatti, another major discrepancy between FDA and EMA oversight is how the two agencies view the use of PFS as an endpoint in registration trials. Although both agencies agree that overall survival is a more clinically relevant endpoint than PFS, the EMA accepts PFS if it measures a clinical benefit, whereas the FDA tends to view it as a surrogate for overall survival.
From page 70...
... With adaptive licensing, in contrast, after initial license of the drug, the number of treated patients grows more slowly due to restrictions on use, and the patient experience is captured, contributing real-world information about the safety and effectiveness of the drug (see Figure 5)
From page 71...
... FIGURE 5  Adaptive licensing captures more of the patient experience, contributing more real-world information about the safety and effectiveness of drugs. NOTE: A = traditional licensing; B = adaptive licensing; RCT = randomized controlled trial.
From page 72...
... For example, the FDA may decide to withdraw a drug from the market or alter its label based on adverse event reports, which are essentially case reports, he noted. Unlike clinical trials, which have strict conditions for patient participation, observational studies have the advantage of better detecting drug effects in the "real world," when they are combined with other medications or influenced by concomitant conditions, Eichler added.
From page 73...
... IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM 73 to position the NCTN groups to play a critical role in the development of more targeted therapies." Doroshow concluded that "it's remarkable that we can, in a financially tight time, come together to understand where the most important science is and what critical infrastructures we need to allow that science to go forward. We have done our job to modernize the system."


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